S21 all

Mortality Attributable to tobacco –
A Global Report

E Tursan d’Espaignet

Tobacco Free Initiative
WHO Geneva

tursandespaignet@who.int

WHO Global Report: Mortality Attributable
to Tobacco

 Estimates for high, low and middle income
countries.

 Effects of direct use of smoking (and
smokeless) tobacco among adults aged 30+
for communicable and non-communicable
diseases.

Contents of the Report

 Builds on global estimates
for 2004 provided in WHO
Report “Global Health
Risks: Mortality and
burden of disease
attributable to selected
major risks” , 2009.

 Expansion to provide data
at WHO Regional and
country levels

The global burden of tobacco use

 Tobacco is the only legal drug that kills many of its users
when used exactly as intended by manufacturers.

 Tobacco kills:
– Direct tobacco smoking: 5 million people / year
– Second hand smoke: 600,000 people / year
– More than tuberculosis, HIV/AIDS and malaria combined

 If effective measures are not urgently taken, tobacco
could, in the 21st century, kill over 1 billion people:

999,999,999 + 1

The global burden of tobacco use

 Use of tobacco among adults in developing
countries is increasing.

 Accelerating rates of tobacco among women.

 Significant social and economic handicap for
families, communities and governments.

 Contributes to family poverty.

Global Voluntary NCD Targets for 2025
under consideration by Member States

 Relative reduction in current tobacco smoking by
40% by 2025

 Relative reduction in age-standardised death rate
from non-communicable diseases by 25%
(using 2010 as baseline)

Surveillance of tobacco

 Art. 20 of the WHO FCTC requires parties to adopt
standard methods of data collection to measure
magnitude, patterns, determinants and consequences
of tobacco use and exposure.

 Much of WHO activities until now has been on
measuring the magnitude of the problem through youth
and adult surveys.

 WHO is now also monitoring outcomes:
- Mortality report
- Pregnancy report (mid-late 2012)

Method of calculating mortality
attributable to tobacco
 The Population Attributable Fraction (PAF) method is
the proportion of deaths that may be attributed to
exposure to tobacco (or any other risk factor).

 The PAF formula is made up of two factors:
– The prevalence (P) of tobacco use in the population;
– The relative risk (RR) of developing a disease among those
who smoke or consume smokeless tobacco, compared with
those who do not use tobacco.

The Smoking Impact Ratio (SIR) method

 To estimate the excess mortality from lung cancer in
smokers in a country’s population relative to the excess
mortality in smokers in the reference population:
- CLC and NLC are lung cancer rates in the population and in •
never smokers in a country’s population
- S*LC and N*LC are lung cancer rates in smokers and never
smokers of the reference population.

 The resulting SIR estimate is then used instead of P in
the PAF formula:

Causes of death are categorised into
3 broad groups
 Group 1: Communicable diseases:
- Tuberculosis
- Lower respiratory tract infection

 Group 2: Non-communicable diseases
- Cancers : Lung cancer
- Cardiovascular diseases: Heart disease, Stroke
- Respiratory diseases – Chronic Obstructive Pulmonary
Disease

 Does not include:
Group 3: Injuries (external causes)

Major Findings

 In 2004, about 5 million adults aged 30 years and
over died from direct tobacco use (smoking and
smokeless) around the globe: 1 DEATH EVERY
6 SECONDS!

 12% of all 30+ deaths attributed to tobacco.

 Mortality higher among men than among women

Findings

Source: WHO Global Report: Mortality Attributable to Tobacco, 2012
http://www.who.int/tobacco/publications/surveillance/rep_mortality_attributable_tobacco/en/i
ndex.html

Communicable disease findings

 5% of all deaths from communicable diseases:

 7% of all deaths due to tuberculosis

 12% of deaths due to lower respiratory infections

NCD Findings
 NCDs account for 14% of all deaths are attributed to tobacco.

 Cardiovascular diseases: 10%

Of those adults aged 30-44 years who died from ischemic heart
disease, 38% of the deaths were attributable to tobacco.

 Cancer deaths: 22%

71% of all lung cancer deaths are attributable to tobacco use.

 Respiratory diseases: 36%

42% of all chronic obstructive pulmonary disease are attributable to
tobacco use.

Stages of the Cigarette Epidemic
on Entering Its Second Century
Michael Thun
Richard Peto
Jillian Boreham
Alan Lopez

WCTOH
Singapore
March, 2012

Full article in 20th Anniversary Edition
of Tobacco Control

2012;21:96-101

Original WHO Model
Four Stages of the Cigarette Epidemic

Source: Lopez et al. Tobacco Control 1994

Value of this Model
• Portrays epidemic as a continuum rather than as a
series of isolated events.
• Allows each country to find itself on this continuum
• Communicates the long delay between the uptake
of widespread smoking and the full eventual
consequences for mortality
• Indicates the paradoxical period in which
prevalence falls but mortality continues to increase
• Shows that without effective tobacco control, the
problem will get much worse.

Disadvantages of original model
• Based on the experience in
economically developed countries
• No corresponding model could be
proposed for developing countries
• The staging criteria based on the
comparative levels of smoking &
mortality in men and women.
• Clearly not applicable in China or India.

Methods
• Assess trends in smoking-attributed mortality
by sex in 41 developed countries from 1950-
”present” using Peto-Lopez indirect method.
• Emphasize ages 35-69
• Review data on smoking prevalence in GATS
& GYTS
• Assess applicability of the model in countries
at various levels of economic development
• Project the trends in prevalence & smoking-
attributed mortality forward through 2025.

Results
1. The original model still provides a
reasonably useful description of the
epidemic in many developed
countries.
• Prevalence has decreased in both sexes,
although more slowly than predicted
• Smoking-attributed deaths are decreasing in
men but increasing or have reached a plateau
in women.

Male and female smoking prevalence
have converged at younger ages in
most high resource countries (& have
crossed over at all ages in Sweden).

Trends in smoking-attributed deaths in
four high resource countries, 1950-2005
Australia Netherlands

50 50

45 45

40 40

35 35

30 30

Percent
Percent

Male Male
25 25
Female Female
20 20

15 15

10 10

5 5

0 0
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

UK US

50 50

45 45

40 40

35 35

30 30
Percent
Percent

Male Male
25 25
Female Female
20 20

15 15

10 10

5 5

0 0
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

Percent indicates percentage of all deaths attributed to smoking in age range 35-69.

However, the staging system in original
model does not fit China or India

Source: Lopez et al. Tobacco Control 1994

Solution

• Allow the stage of the epidemic to differ in
men and women.
• Designate these stages based on sex-
specific data

Evolution of the Smoking Epidemic
in Men
% of smokers among adults % of deaths caused by
smoking
STAGE 1 STAGE 2 STAGE 3 STAGE 4
70 40

35
60
% male smokers
30
50
% male deaths
25
40
20

30
15

20
10

10
5

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Sub-Saharan Africa China, Norway Western Europe, USA, UK, Australia
Southeast Asia Greece, Latin American

Evolution of the Smoking Epidemic
in Women
% of deaths caused by
% of smokers among adults smoking
STAGE 1 STAGE 2 STAGE 3 STAGE 4
70 40

35
60

30
50

25
40
20

30
15
% female smokers
20
% female deaths 10

10
5

0 0
0 10 20 30 40 50 60 70 80 90 100 110 120
Sub-Saharan Africa Eastern and Southern Western Europe, USA, UK,
Europe Australia
Southeast Asia, China

Conclusions
1. Predictions from the model fit well qualitatively
with recent trends in high resource countries.
2. Also reasonably compatible with trends among
men in developing countries
3. The stages as defined by the original model are
not applicable to China or India
4. Modifying the model to allow different stages for
men and women will improve its generalizability
to developing countries.

Updated data on smoking-related
deaths in 41 countries available at:

• http://tobaccocontrol.bmj.com/content/21/2.toc

• http://www.ctsu.ox.ac.uk/~tobacco/

The global burden of deaths from tobacco is
shifting from developed to developing
countries
Tobacco deaths 2000 Tobacco deaths 2030
Developed 2 million 3 million
Developing 2 million 7 million

By 2030, 7 of every 10 tobacco attributable deaths
projected to be in developing countries

World Health Organization. 1999. Making a Difference. World Health Report. 1999.
Geneva, Switzerland

Smoking-attributed mortality estimates
in original model based on U.S. data

US data updated to most recent year available:
Prevalence through 2010, Smoking-Attributed Mortality
through 2005
% of smokers among adults % of deaths caused by
STAGE 2 STAGE 3 STAGE 4 smoking
STAGE 1
70 40

35
60
% male smokers

30
50
% male deaths
25
40
% female smokers
20

30
15

20
% female deaths 10

10
5

0 0
0 10 20 30 40 50 60 70 80 90 100
1900 1920 1940 1960 1980 2000

Trends in Cigarette Smoking Prevalence (%),
by Sex, Adults 18 and Older, US, 1965-2010

60
(52%)
50
Prevalence (%)

40

30 Men (21.5%)
(34%)
20
Women
(17.3%)
10

0
1965
1974
1979
1983
1985
1990
1992
1994
1995
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Year

Source: National Health Interview Survey, 1965-2010, National Center for Health Statistics, Centers for Disease
Control and Prevention, 2011.

Prevalence of smoking - UK
Men Women

70 60

60 50
50
40
Prevalence

40
30
30
20
20

10 10

0 0
46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01-
50 55 60 65 70 75 80 85 90 95 00 05 50 55 60 65 70 75 80 85 90 95 00 05
Year Year
Source: IMASS v4, 2010

Australia
Men Women

70 70

60 60

50 50
Prevalence

40 40

30 30

20 20

10 10

0 0
46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01- 46- 51- 56- 61- 66- 71- 76- 81- 86- 91- 96- 01-
50 55 60 65 70 75 80 85 90 95 00 05 50 55 60 65 70 75 80 85 90 95 00 05
Year Year
Source: IMASS v4, 2010

Epidemic lags in women in all Southern
and most Eastern European countries
Greece Poland

50 45

45 40
40
35
35
30
30
Percent

Percent
Male 25 Male
25
Female 20 Female
20
15
15

10 10

5 5

0 0
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

Russia Romania

50 50

45 45

40 40

35 35

30 30
Percent
Percent

Male Male
25 25
Female Female
20 20

15 15

10 10

5 5

0 0
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

Trends in lung cancer death rates
among men in U.S., U.K. and Commonwealth

United Kingdom

United States

Canada
New Zealand
Australia

Lung cancer mortality age 35-69,
for selected countries, 1960-2000
UK US France Hungary

Peto R, Lopez AD et al. http://www.ctsu.ox.ac.uk/~tobacco/index.htm

Trends in lung cancer death rates among
men in Southern Europe

Italy
Greece
Spain

Source: Li et al. (2011) NEJM Vol. 364:25

Active Smoking, Secondhand Smoke
and Breast Cancer Risk
Kenneth C. Johnson, PhD

Department of Epidemiology and
Community Medicine

Faculty of Medicine
University of Ottawa

March 23, 2012

World Conference on Tobacco or Health
Singapore

Overview
 Passive smoking meta-analyses
 3 Interpretations 2004, 2005, 2006
 Canadian Expert Panel 2009
 Active smoking risk
 Conclusions

 Passivesmoking
 Secondhand smoke
 Involuntary smoking
 Environmental tobacco smoke (ETS)

Expert Panel Approach
Based on the weight of evidence from:
- epidemiologic studies,
- toxicological studies and
- understanding of biological
mechanisms
What can be concluded about the
relationships between:
- passive smoking and breast cancer
- active smoking and breast cancer

20 Mammary Carcinogens in SHS

Acrylamide
Acrylonitrile
1,3-Butadiene
Isoprene
Nitromethane
Propylene Oxide
Dibenz[a,h]anthracene
Vinyl chloride
4-Aminobiphenyl
Urethane
Benzene
Nitrobenzene
Benzo[a]pyrene
ortho-Toluidine
Dibenzo[a,e]pyrene
Dibenzo[a,i]pyrene
Dibenzo[a,l]pyrene
N-Nitrosodiethylamine
N-Nitrosodi-n-butylamine

Undiluted Sidestream Tobacco
Smoke versus Mainstream Smoke
Examples Ratio in Sidestream to
Mainstream Smoke

- Carbon monoxide 2.5-15 times as much
- Nitrogen Oxides 3.7-12.8 times
- Nicotine 1.3-21 as much
- Benzene 8-10 times as much
- Formaldehyde 50 times as much
- NNK 1-22 times as much
- Benz(a)pyrene 2.5-20 times as much
- Nickel 13-30 times as much
- Tar 1.1-15.7 times

Source: Hoffmann and Hecht, 1989

Meta-analysis of Studies of Passive
Smoking and Breast Cancer
• 20 Studies published by end of 2004
• 8 cohort studies, 12 case control studies
• 7 in Asia, 3 in Europe, 10 in North America
• 9 before 2000, 11 since 2000
• Disease endpoint (18 diagnosis, 2 death)
• Significant age restrictions in 7 studies
• Control for potential confounders in most studies

Reference: Johnson, KC. Accumulating Evidence on Passive and
Active Smoking and Breast Cancer Risk Int J Cancer, May 2005

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Thank god! A panel of experts


Conclusions – Cal EPA Report (2005)
Passive Smoking & Breast Cancer
 “Overall, the weight of evidence
(including toxicology of tobacco
smoke constituents, epidemiological
studies, and breast biology) is
consistent with a causal association
between ETS exposure and breast
cancer in younger, primarily
premenopausal women”

Surgeon General’s Conclusion
“ The evidence is suggestive but not
sufficient to infer a causal relationship
between secondhand smoke and breast
cancer.”

California EPA and Surgeon General
found similar passive risk estimates
California EPA Report Surgeon Generals
2005 1 Report 20062

Exposure n Relative Risk N Relative Risk
(95% CI) (95% CI)

All studies 19 1.25 (1.08-1.44) 21 1.20 (1.08-1.35)

Premenopausal/ 14 1.68 (1.31-2.15) 11 1.64 (1.25-2.14)
Women < 50
Premenopausal 5 2.20 (1.69-2.87) 6 1.85 (1.19-2.87)
with lifetime
exposure
assessment

A Question of Interpretation:
Balancing Concerns
Results from Cohort Studies versus Case-control Studies?

Exposure misclassification versus Recall and Response Bias?

Confounding by Alcohol?

Is the unexposed group different in other ways?

Premenopausal risk and No Postmenopausal Risk?

Passive but No Active Smoking Risk?

Reference: Rothman & Greenland. Modern Epidemiology 2nd Ed.

Studies of Excess Lung Cancer Risk for
Non-Smokers From Second-Hand Smoke
250
+35-220% +50-210%
200
USA 1994
150 Europe 1998
Excess Lung Sweden 1998
Cancer Risk Germany 1998
(Percentage) 100
+1-25% China 1999
Germany 2000
50 China 2000
Canada 2001
0
Home and Work - Work Only -
Spousal
Higher Exposure Higher Exposure

Type and Level of Exposure

SHS and Breast Cancer Studies since 2006
 Lissowska et al. (2007, 2007b) lifetime SHS assessment
 women under age 45, total SHS 1.00, 1.36, 1.52, 2.02 (0.94-4.36)

 Roddam et al. (2007) spousal exposure only (41% exposed)
 risk increases not found

 Lin et al. (2008) Japan Collaborative Cohort Study, age 40-79; 196
never smoker cases; 8 ever smoker cases,
 no analyses with unexposed referent group

 Pirie et al. (2008) SHS, age 0, 10, current spousal (age 53-67) (11%
exposed) risk increases not found

 Pirie et al. (2008) Meta-analysis retrospective/prospective; no
subcategories

SHS and Breast Cancer Studies Since 2009
 Ahern et al. (2009) lifetime assessment,
 No consistent risk increases found

 Reynolds et al (2010) California Teachers Cohort
– Updated evaluation of SHS
– Lifetime exposure assessment

 Luo et al (2011) – Women’s Health Initiative Cohort (U.S)
 - Lifetime Exposure Assessment

 Xue et al (2011) – Updated evaluation of the Harvard
Nurses’ Health Cohort
 - exposure assessment limited
 - occupational assessment limited to current exposure in
1982

Secondhand Smoke and Breast
Cancer Risk – New Cohort Studies
SHS Exposure California Women’s Health
Teachers Cohort[48] Initiative Cohort[27]
Adjusted HR Adjusted HR (95%
(95% CI) CI)

No reported lifetime 1.00 1.00
exposure
Any childhood exposure 1.06 (0.94-1.19) 1.19 (0.93-1.53)
Any adult home exposure 1.04 (0.92-1.16) 0.91 (0.70-1.19)
Any workplace exposure 1.02 (0.93-1.13) 1.01 (0.82-1.26)

Highest cumulative lifetime 1.26 (0.99-1.60) 1.32(1.04-1.67)
exposure (vs. no lifetime
exposure from any source).

Surgeon General’s Basic Premise
“There is substantial evidence that active
smoking is not associated with an
increased risk of breast cancer in studies
that compare active smokers with persons
who have never smoked.”

Surgeon General’s Report 2006 (p 446)

Surgeon General Relies Heavily on
53 Study Collaborative Reanalysis

“In a pooled analysis of data from 53 studies, the
relative risk for women who were current smokers
versus life-time non-smokers was 0.99 (95% CI,
0.92-1.05) for the 22,225 cases and 40,832 controls
who reported not drinking alcohol. The effect of
smoking did not vary by menopausal status.”

Surgeon General’s Report 2006 (p 446)

Overall risk for premenopausal
breast cancer and smoking – greater
than overall alcohol risk?
Active smoking (non-drinkers) Relative Risk
current vs never 0.99 (0.92-1.05)
ever vs never 1.03 (0.98-1.07)
ever vs never premenopausal 1.07 (0.8-1.4)

Alcohol Relative Risk
ever vs never drinkers 1.06
Alcohol risk = 7.1% risk increase per drink/day

Increased Breast Cancer Risk with Active
Smoking in Recent Cohort Studies
Exposure
Study Measure Relative Risk (95% CI)

Cancer Prevention II 40+ years 1.38 (1.05-1.83)
40+ cig/day 1.74 (1.15-2.62)
Nurses Health Study 15+ cig/day 1.5 (1.1-2.0)
California Teachers 31 pack-yrs 2.05 (1.20-3.49)
(premeno)
Canadian Breast Screening Cohort 40+ years and 1.83 (1.29-2.61)
>20 cig/day
Norwegian/Swedish Cohort Study 20+ pack-yrs 1.46 (1.11-1.93)
Initiation 10-14 1.48 (1.03-2.13)
Japanese Public Health Center Ever active 3.9 (1.5-9.9)
(premeno)
References: Calle et al. 1994; Hunter et al. 1997; Reynolds et al. 2004; Terry et al. 2002; Gram et al. 2005;
Hanaoka et al 2004.

Smoking Pack-years, NAT2 Acetylators Status,
Menopausal Status and Breast Cancer Risk

NAT2 Slow Acetylators NAT2 Rapid Acetylators
Premenopausal Postmenopausal Premenopausal Postmenopausal
Type of Pack-
RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI)
Analysis years
Meta- Never 1.00 1.00 1.00 1.00
Analysis active

<20 1.21 (1.00-1.45) 1.28 (1.08-1.50) 1.00 (0.80-1.24) 1.12 (0.93-1.36)
>20 1.47 (1.08-2.01) 1.41 (1.15-1.72) 1.34 (0.94-1.89) 0.98 (0.77-1.26)

Source: Ambrosone et al. 2008

Smoking Pack-years, NAT2 Acetylators Status,
Menopausal Status and Breast Cancer Risk

NAT2 Slow Acetylators NAT2 Rapid Acetylators
Premenopausal Postmenopausal Premenopausal Postmenopausal
Type of Pack-
RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI)
Analysis years
Meta- Never 1.00 1.00 1.00 1.00
Analysis active

<20 1.21 (1.00-1.45) 1.28 (1.08-1.50) 1.00 (0.80-1.24) 1.12 (0.93-1.36)
>20 1.47 (1.08-2.01) 1.41 (1.15-1.72) 1.34 (0.94-1.89) 0.98 (0.77-1.26)

Pooled Never 1.00 1.00 1.00 1.00
Analysis active
<20 1.05 (0.86-1.28) 1.23 (1.03-1.46) 0.91 (0.72-1.16) 1.10 (0.89-1.35)
>20 1.49 (1.08-2.04) 1.42 (1.16-1.74) 1.29 (0.89-1.86) 0.88 (0.69-1.13)

Source: Ambrosone et al. 2008

Cohort Studies of Active Smoking and Breast Cancer Risk
(>500 cases) by Highest Exposure Categories
Youngest age of
First author, year
initiation

Calle (1994) 1.59 (1.17-2.15)

Egan (2002) 1.19 (1.03-1.37)

Al-Delaimy(2004) 1.29 (0.97-1.71) 8 of 8 positive;
Reynolds (2004) 1.17 (1.05-1.30) 4 of 8 Stat Sig
Lawlor (2004)

Gram (2005) 1.48 (1.03-2.13)

Olson (2005) 1.12 (0.92-1.36)

Cui (2006) 1.11 (0.97-1.28)
Ha (2007) 1.48 (0.77-2.84)

Source: Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk, 2009

by Highest Exposure Categories

Youngest age of Longest duration
First author, year
initiation before pregnancy

Calle (1994) 1.59 (1.17-2.15)

Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31)

Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52)

Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 9 of 9 positive;
1.06 (0.72-1.56) 4 of 9 Stat Sig
Lawlor (2004)
1.04 (0.67, 1.59)
Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37)

Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25)

Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25)

Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11


6 of 6 positive;
Youngest age of Longest duration Longest
First author, year 3 of 6 Stat Sig
initiation before pregnancy duration

Calle (1994) 1.59 (1.17-2.15)

Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31) 1.05 (0.90-1.21)

Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52) 1.21 (1.01-1.45)

Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 1.15 (1.00-1.33)
1.06 (0.72-1.56)
Lawlor (2004)
1.04 (0.67, 1.59)
Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37) 1.36 (1.06-1.74)

Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25) 1.18 (1.00-1.38)

Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25) 1.50 (1.19-1.89)

Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11


Youngest age of Longest duration Longest Highest pack-
First author, year
initiation Before pregnancy duration years

Calle (1994) 1.59 (1.17-2.15) 1.38 (1.05-1.83)

Egan (2002) 1.19 (1.03-1.37) 1.13 (0.99-1.31) 1.05 (0.90-1.21)

Al-Delaimy(2004) 1.29 (0.97-1.71) 1.10 (0.80-1.52) 1.21 (1.01-1.45)

Reynolds (2004) 1.17 (1.05-1.30) 1.13 (1.00-1.25) 1.15 (1.00-1.33) 1.25 (1.06-1.47)
1.06 (0.72-1.56)
Lawlor (2004)
1.04 (0.67, 1.59)
Gram (2005) 1.48 (1.03-2.13) 1.27 (1.07-1.37) 1.36 (1.06-1.74) 1.46 (1.11-1.93)

Olson (2005) 1.12 (0.92-1.36) 1.21 (1.01-1.25) 1.18 (1.00-1.38) 1.15 (0.96-1.37)

Cui (2006) 1.11 (0.97-1.28) 1.13 (1.01-1.25) 1.50 (1.19-1.89) 1.17 (1.02-1.34)

Ha (2007) 1.48 (0.77-2.84) 1.78 (1.27-2.49)11 5 of 5 positive,
4 of 5 statistically sig

Table 13: Cohort Studies – Age of Smoking
Initiation And Breast Cancer Risk

Earliest Age Smoking Relative Risk
First Author, Year Began Category Cutoff (95% CI)

Reynolds et al. (2004) <20 1.17 (1.05-1.30)

Olson et al. (2005) <19 1.12 (0.92-1.36)

Xue et al (2011) <18 1.04 (0.99-1.11)

Cui et al. (2006) <16 1.11 (0.97-1.28)

Al-Delaimy et al. (2004) <15 1.29 (0.97-1.71)

Gram et al. (2005) <15 1.48 (1.03-2.13)

Ha et al. (2007) <15 1.48 (0.77-2.84)

US Radiologic Technologists Cohort:
Smoking Before 1st Birth

Reference: M. Ha, K. Mabuchi, A. J. Sigurdson, D. M. Freedman, M. S. Linet, M. M. Doody and M. Hauptmann,
Smoking cigarettes before first childbirth and risk of breast cancer. Am J Epidemiol 166, 55-61 (2007).

Smoking After 1st Birth


Smoking Risk Before and After 1st Birth


Source: Xue et al. Cigarette smoking and the incidence of breast cancer. Arch Intern Med 2011; 171(2):125-133.

Harvard Nurses Health Study Cohort
Smoking before First Birth and
Increased Breast Cancer Risk

Lung Cancer and Passive Smoking

14 Studies of Passive Smoking and Lung Cancer:
Causal connection established 1986

i

Reference: Wald et. al. BMJ 1986; 293: 1217-22.

Cumulative Meta-analysis of Spousal ETS
Exposure and Lung Cancer Risk 1981-1999

Secondhand Smoke Conclusion
Based on the weight of evidence presented by:
- the California EPA
- the Surgeon General, and
- strong recent evidence of an active smoking-
breast cancer risk,

The Expert Panel concluded that:

The relationship between secondhand smoke
and breast cancer in younger, primarily
premenopausal women is consistent with
causality.

Active Smoking Conclusion
Based on the weight of evidence from:
- epidemiologic studies,
- toxicological studies and
- understanding of biological mechanisms,

The Expert Panel concluded that:

The relationships between active smoking and
both pre- and postmenopausal breast cancer
are consistent with causality.

Lung disease in relation to
tobacco exposure
Ioana Munteanu , Fl. Mihaltan
“Marius Nasta” Institute of
pneumology Bucharest Romania

• Effects of cigarette smoke on the lung
• History
• Lung diseases

• Effects of cigarette smoke on the lung
• History
• Lung disease

Europe - 650,000 deaths / year are attribute to smoking

THE MECHANISM OF INDUCED LUNG INJURY
850-900
Pathology of the Lung
European Respiratory Society Monograph, Vol. 39, 2007E
TOBACCO SMOKE dited by W. chemicals
4000 Timens and H.H. Popper
60 carcinogenic

CILIARY CLEARANCE DISTURBANCE OXIDANTS,
OXIDE, AROMATIC HYDROCARBONS,
ALDEHYDES, NITROSAMINES
ACIDS,
AMMONIA RETENTION OF MUCUS AND TOXINS
GROWTH SIGNALS
LOCAL IRRITATION OF THE
DESTRUCTION OF CHROMOSOME
RESPIRATORY EPITHELIUM
AND DNA
INJURY / CELL DEATH
EXPRESSION OF ONCOGENES
INFLUX OF NEUTROPHILS
INFECTION
CARCINOGENESIS
INFLAMMATION

COPD AND OTHER LUNG CANCER
INFLAMMATORY LUNG DISEASES

Pulmonary disease in relation to
smoking

• Diseases in which smoking is directly involved and
has negative effects on their evolution

– COPD
– Lung cancer

Risk of developing a disease caused by
smoking
• As compared to nonsmokers, smoking is
estimated to increase the risk of:
– men developing lung cancer by 23 times,

– women developing lung cancer by 13 times, and

– dying of chronic obstructive lung diseases (such as
chronic bronchitis and emphysema) by 12 to 13
times.
http://www.cdc.gov/tobacco/data_statistics/fact_sheets/he
alth_effects/effects_cig_smoking/

Pulmonary disease in relation to
smoking
• Diseases whose evolution is worsened by smoking
• Chronic inflammatory diseases
Asthma
Emphysema due to α1-antitrypsin deficiency
Chronic bronchitis

• Neoplasms
Cavum tumors
Tumors of the mouth
Laryngeal tumors

• Infectious Diseases
Rhinitis, pharyngitis, pneumonia, influenza, tuberculosis

• Interstitial lung Disease
Pneumoconiosis, idiopathic pulmonary fibrosis, idiopathic interstitial pneumonia,
bronchiolitis

History
In 1950 , Prof . R. Doll began his studies on the role
of smoking as risk factor in lung cancer. He published
in the British Medical Journal his conclusions;
"The risk of developing the disease increases in
proportion to the amount smoked. It may be 50
times as great among those who smoke 25 or more
cigarettes a day as among non-smokers."

In 1964 the Association of Surgeons of
the U.S. presents the first cause and effect
relationship between smoking and lung
cancer

1981: Earliest evidence of the passive smoking involvement in lung cancer
development Takeshi Hirayama (Japan)

• 1992 Environmental Protection Agency's
Respiratory Health Effects of Passive Smoking:
Lung Cancer and Other Disorders complete
their research on ETS
•
ETS was included in class A carcinogens, in
the same category as asbestos, benzene and
radon.

• More than 3,000 lung cancer deaths per year
were attributed to ETS.

• The U.S. Surgeon General : The lung cancer risk
for a nonsmoker whose spouse is a smoker is
20-30% higher.

PATHOGENESIS AND PATHOPHYSIOLOGY OF LUNG LESIONS INDUCED
BY TOBACCO

Cigarette smoke Oxidants

Inflammation in the airways and lung

Bronchial biopsies showed :

Chronic inflammatory changes with increased no. of specific
inflammatory cells

Structural remodeling due to repeated injury and repair mechanisms

Int. J. Environ Res. Public Health 2009

Lifetime risk of developing chronic obstructive
pulmonary disease
Dr Andrea S Gershon 2010
• Prospective study : All individuals free of COPD in 1996 were monitored for up to 14 years

• The cumulative incidence of physician-diagnosed COPD over a lifetime adjusted for the competing risk of
death was calculated
• Results were stratified by sex, socioeconomic status and a rural or urban setting.

• Findings
A total of 579 466 individuals were diagnosed with COPD by a physician over the study period.
– The overall lifetime risk of physician-diagnosed COPD at age 80 years was 27,6%.
– Lifetime risk was higher in men than in women (29,7% vs 25,6%),
– Individuals of lower socioeconomic status had an increased risk as compared to those of higher
socioeconomic status (32,1% vs 23,0%),
– The risk was higher in individuals who lived in a rural setting than in those who lived in an urban
setting (32,4% vs 26,7%).
• Interpretation
• About one in four individuals are likely to be diagnosed and receive medical
attention for COPD during their lifetime. Clinical evidence-based approaches, public health
action, and more research are needed to identify effective strategies to prevent COPD and ensure that
those with the disease have the highest quality of life possible

Smoking Cessation: Improvement in
Postbronchodilator FEV1 Decline
Susceptible smokers develop significant lung function decline
Sustained Quitters
2.9 Continuous Smokers
Postbronchodilator FEV1 L

2.8

2.7

2.6

2.5 The Lung Health Study (LHS)
(N=5887) aged 35 to 60 years
2.4 5 years follow up

Screen 2 1 2 3 4 5
Follow up (y)
Anthonisen et al. JAMA. 1994;272(19):1497-1505; Kanner et al. Am J Med. 1999;106(4):410-416.

COPD

The exact role of smoking cessation on airway inflammation in
patients with COPD remains unknown

Studies- Inflammation persists despite smoking cessation

EXPLANATION
•Persistence of an inflammatory trigger that maintains ongoing
local inflammatory response
•In COPD, persistent inflammation may be due to destruction
of tissue in the airways induced by smoking

NEW HYPOTHESES - COPD may have an autoimmune component,
contributing to persistent inflammation even after smoking
cessation
Int. J. Environ Res. Public Health 2009

Predictors of Mortality in Patients with Stable
COPD Esteban, 2008,

Five-year prospective cohort study.
600 stable COPD patients recruited consecutively.
Which clinical factors are associated with mortality in patients with stable COPD

Asthma

smoking is a risk candidate for development of asthma

smoking is more prevalent in individuals with asthma than in those without

smoking is associated with decreased asthma control and increased
risk of mortality and asthma attacks and exacerbations

smokers with and without asthma may have different risk factors for
smoking onset as well as different smoking motives and outcome expectancies

smoking cessation is associated with improvements in lung functioning
and asthma symptoms.

Eur Respir J 2004; 24:
822–833

Effects of smoking cessation on airflow obstruction and quality
of life in asthmatic smokers. Jang AS,Korea 2010

22 continue to smoke
32 subjects
10 quit smoking

The lung cancer risks of smoking vary with the
quantitative aspects of smoking

• Duration of smoking is the stronger
determinant of lung cancer risk in some
analyses ( Doll and Peto)
• Starting age is linked to duration of smoking
• Depth of inhalation
• Number of cigarettes smoked
• Years as nonsmoker
• The cigarette type

THE LUNG CANCER RISK INCREASEs EXPONENTIALLY WITH THE NUMBER OF YEARS
AND THE NUMBER OF CIGARETTE SMOKED BY DAY

Lubin J H , Caporaso N E Cancer Epidemiol Biomarkers Prev
2006;15:517-523

Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease
Incidence and Predicting Factors
Juan P. de Torres, Am. J. Respir. Crit. Care Med. October 15, 2011

• A cohort of 2,507 patients without initial clinical or
radiologic evidence of lung cancer was monitored over
a period of 60 months on average (30–90) .
• 215 patients with COPD developed lung cancer
(incidence density of 16.7 cases per 1,000 person-
years)
• Squamous cell carcinoma is the most frequent
histologic type.
• Older patients with milder airflow obstruction (GOLD I
and II) and lower body mass index.
• Lung cancer incidence was lower in patients with worse
severity of airflow obstruction.

Tobacco-attributable cancer burden in
the UK in 2010, DM Parkin

Pack-Years of Cigarette Smoking as a Prognostic Factor
in Patients With Stage IIIB/IV Nonsmall Cell Lung Cancer
Janjigian, Cancer 2010

2010 patients with stage IIIB/IV NSCLC between June 2003 and March 2006.

Infectious diseases - tuberculosis

The association between smoking and tuberculosis has
been investigated since 1918

Int J Tuberc Lung Dis. 2007 Mar;11(3):258-62.
Associations between tobacco and tuberculosis

The reduction of tuberculosis risks by
smoking cessation
Wen, et al.--2010

Smoking and mortality from tuberculosis and
other diseases in India: retrospective study of
43 000 adult male deaths and 35 000 controls
Gajalakshmi, et al.--2009

Tobacco smoking and pulmonary
tuberculosis
Kolappan, Gopi--2002

Genetic and Lifestyle Modifiers of
Cancer
Smoking on Disease Risk
Woon-Puay Koh
Saw Swee Hock School of Public Health
National University of Singapore

List of cancers associated with
cigarette smoking………
 Lung
 Mouth and pharynx
 Larynx
 Esophagus
 Stomach
 Pancreas
 Liver
 Cervix
 Bladder
 Kidney
 Colorectum
 Breast

What modifies a smoker’s risk of cancer?

 Risk of lung cancer in smokers
 Body mass index

 Risk of colorectal cancer in smokers
 Genetic polymorphism

 Findings from The Singapore Chinese Health
Study

Singapore Chinese Health Study
Eligibility criteria: Singapore Chinese, housing estate residents, ages
45-74 years
Recruitment period: April 1993 to December 1998
Cohort size: Total of 63,257, with 35,298 women and 27,959 men
Baseline data: In-person interview, focus on current diet-using
validated 165-item food frequency questionnaire,
smoking, alcohol, physical activity, occupational
exposures, detailed menstrual and reproductive
history from women
Biospecimen : Blood/buccal cells and spot urine from consenting
subjects between 1999 and 2004. A total of 32,575
subjects contributed biospecimens, representing
51% of the cohort.
Follow-up: Disease registry, death registry, address/phone
updates via linkage and 2 follow-up interviews

Cigarette smoking
 31% ever smokers among the 61,321 subjects
Men (n=27,292) Women (n=34,028)
Never Former Current Never Former Current
Percent 42.2% 21.4% 36.4% 91.3% 2.5% 6.2%
 Heavy smokers (12%):
 Started to smoke before 15 years of age AND smoked
at least 13 cigarettes per day
 Light smokers (88%):
 Started to smoke after 15 years of age OR smoked 12
or less cigarettes per day
 Compared to never smokers, heavy smokers were older,
less educated, more likely to be male, had lower body
mass index (leaner), and drank more alcohol

Cigarettes and Lung Cancer Risk
1,042 incident lung cancer cases in this cohort
after a mean follow-up of 10.7 years

Smoking Lung cancer Lung cancer
status RR (95% CI)* # sticks/day RR (95% CI)*
Never 1.00 Never 1.00
2.24 (1.81-2.78) 1-12 4.32 (3.55-5.23)
Former
13-22 6.61 (5.46-8.02)
Current 5.85 (4.99-6.87)
23+ 9.49 (7.58-11.88)
P for trend <0.0001
*Hazard ratios (HRs) were adjusted for age at baseline, sex,
dialect group and year of interview; CI, confidence interval.

Koh et al Br J Cancer (2010);102:610-4.

Body Mass Index in Relation to Lung
Cancer Risk by Smoking Status
Never Former Current
Body Mass smokers smokers smokers
Index (kg/m2) Adj. HR Adj. HR Adj. HR
(95% CI)* (95% CI)* (95% CI)*
<20 1.00 1.00 1.00

20-<24 1.02 (0.71-1.46) 0.92 (0.57-1.48) 0.81 (0.67-0.99)

24-<28 0.72 (0.46-1.10) 1.01 (0.59-1.74) 0.62 (0.46-0.82)

28+ 0.81 (0.46-1.44) 0.97 (0.44-2.12) 0.50 (0.28-0.88)

P for trend 0.08 0.89 0.0001


Smoking and lung cancer risk by levels of BMI
<20 kg/m2 20-<24 kg/m2 24-<28 kg/m2 >=28 kg/m2
Smoking
status
HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)*

Never 1.00 1.00 1.00 1.00

Former 2.46 1.97 2.96 1.99
(1.40-4.32) (1.48-2.62) (1.84-4.76) (0.88-4.52)

Current 7.21 5.20 5.50 3.21
(4.84-10.75) (4.22-6.41) (3.64-8.32) (1.58-6.51)


Smoking and lung cancer risk by levels of BMI
<20 kg/m2 20-<24 kg/m2 24-<28 kg/m2 >=28 kg/m2
HR (95% CI)* HR (95% CI)* HR (95% CI)* HR (95% CI)*

Cigarettes per day (risk relative to never smokers)
1-12 6.18 3.65 3.65 2.90
(3.98-9.58) (2.82-4.73) (2.12-6.28) (1.15-7.27)
13-22 7.92 6.39 5.41 2.21
(5.01-12.53) (4.98-8.20) (3.23-9.05) (0.71-6.86)
23+ 11.12 8.53 9.01 6.37
(6.60-18.70) (6.35-11.50) (5.04-16.10) (2.10-19.30)
P trend <0.0001 <0.0001 <0.0001 0.0001


Biological plausibility
 Body mass index influences a smoker’s risk
of lung cancer
 Lean smokers have increased oxidative DNA
damage relative to obese smokers
 Lean smokers have increased susceptibility
to tobacco carcinogens-induced DNA
damage

Public Health Implication
 Rapid increase in smoking prevalence in
developing countries such as China and India
in which people still have relatively low body
weights

 The adverse effect of smoking would be
stronger in the developing countries than the
developed world

Smoking and Colorectal Cancer Risk

“Lifestyle” cancer
 Obesity
 Western diet
 Physical inactivity
 Smoking

Current smoking and colorectal cancer
risk: Meta-analysis (18 cohort studies)

Tsoi KK et al Clin Gastroenterol Hepatol. 2009;7:682-688

Colonic carcinogens in cigarette
 Polycyclic aromatic hydrocarbons (PAHs) and
heterocyclic aromatic amines (HAAs)
 Metabolic activation to form highly reactive
mutagens that readily react with DNA bases
 Undergo detoxification through conjugation
reactions with the phase II enzymes to be
excreted

GST enzymes
 5 main classes: alpha (GSTA), mu (GSTM), pi
(GSTP), theta (GSTT) and zeta (GSTZ)
 GSTM1, GSTT1 and GSTP1 are detoxification
enzymes that have been known to metabolize
a wide range of carcinogens from tobacco
smoke and diet, including HAAs and PAHs
 High expression in the intestinal tract.
 These GSTs are polymorphic enzymes with
inter-individual variations in enzymatic level
and activity.

GSTM1 and GSTT1 polymorphisms

 The homozygous deletion genotypes of GSTM1
and GSTT1 result in an absence of GSTM1 and
GSTT1 expression

GSTP1 polymorphism
 A transition of adenine (A) to
guanine (G) at nucleotide 313 in
exon 5 of the GSTP1 gene results
in a change from isoleucine (Ile)
to valine (Val) at position 104 in
the amino acid sequence of the
corresponding protein.
 GSTP1 BB and the heterozygous
variant, GSTP1 AB, have been
shown to possess decreased
specific activity and affinity for
substrates

GST/Smoking/Colorectal Cancer

GSTs can deactivate HAAs and PAHs

Hence, individuals with genetically
determined decreaseinin GST
HAAs and PAHs cigarette smoke
enzyme activity may have increased
risk of colorectal cancer risk
associated with smoking
Smokers

Increased risk of Colorectal Cancer

Nested case-control study within the
Singapore Chinese Health Study
 480 incident colorectal cancer cases within
the cohort diagnosed as of April 30, 2005
identified by linkage with nationwide cancer
registry and confirmed by verification of
histological reports or medical notes.
 1167 controls from a random 3% of the
cohort population and who consented to give
us blood

Cigarettes and Colorectal Cancer
Colorectal Colon Rectal
Smoking level OR (95% CI)* OR (95% CI)* OR (95% CI)*

Never 1.00 1.00 1.00
Light smoker 1.16 (0.87-1.54) 0.94 (0.66-1.34) 1.45 (0.99-2.13)
Heavy smoker 2.95 (1.72-5.06) 2.18 (1.11-4.29) 4.12 (2.15-7.88)
P for trend 0.002 0.246 <0.0001

Intensity of smoking is associated with
colorectal cancer risk

Koh et al, Carcinogenesis. 2011; 32:1507-11

GSTs and Colorectal Cancer
GSTM1 OR (95% CI)* OR (95% CI)* OR (95% CI)*
Present 1.00 1.00 1.00
Null 0.92 (0.73-1.16) 0.83 (0.62-1.10) 1.06 (0.77-1.46)

GSTT1 No clear association between CI)*
OR (95% CI)* OR (95% CI)* OR (95%

polymorphisms of GSTM1, GSTT1 or
Present 1.00 1.00 1.00
Null 1.12 (0.89-1.41) 1.23 (0.93-1.61) 1.03 (0.75-1.41)
GSTP1 and colorectal cancer risk
GSTP1 OR (95% CI)* OR (95% CI)* OR (95% CI)*
AA 1.00 1.00 1.00
AB 0.82 (0.63-1.06) 0.86 (0.63-1.18) 0.76 (0.53-1.09)
BB 0.65 (0.35-1.21) 0.74 (0.35-1.58) 0.55 (0.22-1.37)
AB/BB 0.80 (0.62-1.02) 0.85 (0.63-1.14) 0.73 (0.52-1.04)

GSTs and Colorectal Cancer
No. of “null Colorectal Colon Rectal
or low OR (95% CI)* OR (95% CI)* OR (95% CI)*
activity” GST
genotypes
0No clear 1.00
association between number of
1.00 1.00
1genetic polymorphisms of GST 1.06 (0.70-1.61)
1.02 (0.76-1.36) 0.98 (0.68-1.40) enzymes
2 0.95 (0.69-1.31) 0.89 (0.60-1.31) 1.06 (0.68-1.65)
3
and colorectal cancer risk (0.19-1.23)
0.76 (0.44-1.32) 0.95 (0.50-1.78) 0.48
P for trend 0.410 0.601 0.498

Null or low activity genotypes: GSTM1 Null, GSTT1 Null, GSTP1 AB/BB


GSTs, Cigarettes and Colorectal Cancer
With zero GST “null or low activity” genotype (22.5%)

Never 1.00 1.00 1.00
Light smoker 0.82 (0.43-1.55) 0.35 (0.15-0.84) 2.00 (0.81-4.90)
Heavy smoker 1.34 (0.38-4.76) 0.68 (0.14-3.22) 3.23 (0.57-18.1)
P for trend 0.916 0.087 0.085



With one GST “null or low activity” genotype (41.4%)

Never 1.00 1.00 1.00
Light smoker 1.09 (0.70-1.68) 0.86 (0.50-1.49) 1.37 (0.77-2.44)
Heavy smoker 2.43 (1.01-5.86) 2.05 (0.66-6.33) 3.01 (1.05-8.62)
P for trend 0.143 0.732 0.052



With two or three GST “null or low activity” genotypes (36.1%)

Never 1.00 1.00 1.00
Light smoker 1.69 (1.03-2.77) 1.92 (1.04-3.54) 1.39 (0.71-2.72)
Heavy smoker 5.43 (2.22-13.2) 4.25 (1.36-13.3) 6.04 (2.14-17.0)
P for trend 0.0002 0.005 0.003


Biological Plausibility
 The GSTM1/GSTT1/GSTP1 genotypic profile of
a cigarette smoker affects his/her risk of
developing colorectal cancer due to exposure
from colorectal procarcinogens present in
tobacco smoke.
 GST enzymes play important role in the
detoxification of colorectal carcinogens in
tobacco smoke.

Gene-Environment-Smoking Interaction
 Wide variation in cancer incidence among smokers
 A range of genetic and lifestyle factors act as
determinants of a smoker’s risk to cancer by
influencing the uptake and metabolism of tobacco
carcinogens, inflammatory response to the tobacco-
induced lung damage and DNA repair

Gene-Environment-Smoking Interaction
 Understand the mechanistic pathway of
tobacco-linked carcinogenesis
 Identify important pathways of activation
and/or deactivation of tobacco-related
carcinogens
 Explain heterogeneity in risk of smoking-
related cancer
 Identify smokers at higher risk of cancer risk
 Provide strong motivation to quit smoking

Acknowledgement

 Cohort Study Team  Professor Mimi Yu
 Singapore Cancer Registry  Assoc Prof Yuan Jian-Min
 Dr Renwei Wang
 Professor Lee Hin Peng

Supported by Grants from the National Cancer Institute (NIH)

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